Chapter 56: The Chronic Lymphocytic Leukemias

• Chronic lymphocytic leukemia (CLL) is a neoplastic disease characterized by accumulation of small, mature-appearing lymphocytes in blood, marrow, and lymphoid tissues.

• The most prevalent adult leukemia in western societies.

• The age-adjusted incidence rate for CLL in the United States is 4.2/100,000 persons according to the Surveillance Epidemiology and End-Result Program of the National Cancer Institute.

• The age-adjusted incidence rate of CLL worldwide is 2.5/100,000 persons as determined by the International Agency for Research on Cancer of the World Health Organization.

• In 98 percent of patients, the disease is of B-cell lineage; less than 2 percent of patients have T-cell lineage leukemia.

• Approximately 0.8 percent of all cancers and approximately 30 percent of all leukemias annually.

• CLL is very uncommon in Eastern Asia (e.g., Japan and Korea).

Environmental Factors

• There is no exogenous factor (e.g., chemical, solvent) that has been established to increase the risk of CLL.

• Radiation exposure both in the Japanese as a result of the atomic bomb detonations in World War II and in Western cultures in patients treated with radiation for spondylitis and uterine cancers did not show an increased risk of CLL, despite an increased incidence of the acute leukemias and chronic myelogenous leukemia.

• CLL B cells may have receptors for Epstein-Barr virus but are not subject to EBV infection.

Hereditary Factors

• Familial occurrence in some patients.

  — Multiple cases of this leukemia may be found within a single family.

  — May also be found in association with other indolent lymphoproliferative disorders.

  — First-degree relatives of patients with lymphoplasmacytic lymphoma or Waldenström macroglobulinemia (see Chap. 70) have a greater than threefold risk of developing CLL.

• Genetic factors that contribute to increased incidence of CLL:

  — Early studies have associated the risk of developing aggressive CLL with polymorphisms in the gene encoding CD5 (located at 11q13), CD38 (located at 4p15), or tumor necrosis factor-α (TNF-α) and other genes mapping to 13q21.33-q22.2.

  — Disease-susceptibility associated with single nucleotide polymorphisms in or around genes encoding proteins involved in apoptosis or immune regulatory pathways, namely CCNH (located at 5q13.3), APAF1 (located at 12q23), IL16 (located at 15q26.3), CASP8 (located at 2q33.1), NOS2A (located at 17q11.1), and CCR7 (located at 17q21.2).

Immunoglobulin Expression

• The leukemic cells from over 90 percent of patients with CLL express low levels of monoclonal surface immunoglobulin.

• Sixty percent of patients cells express κ light chains and 40 percent with λ light chains.

• Evidence for selection in the immunoglobulin genes expressed by CLL argues that stimulation through the immunoglobulin receptor plays a role in leukemogenesis.

• CLL cells express IgM in 25 percent and both IgM and IgD in over 55 percent of cases and rarely express other immunoglobulin isotypes.

Monoclonal B-Cell Lymphocytosis

• Studies using flow cytometry have found populations of B cells with the phenotype of CLL cells in the blood of healthy individuals.

• These monoclonal B cells coexpress CD5 and CD19 and have low level expression CD20 and CD79b.

• Fourteen percent of healthy first-degree relatives with two or more family members with CLL have circulating monoclonal B cells of the CLL B-cell immunophenotype.

• Approximately 8 percent of healthy individuals over the age of 60 years of age have circulating monoclonal B cells of the CLL phenotype whether or not they have an absolute lymphocytosis.

• Patients with monoclonal B-cell lymphocytosis may develop frank CLL that eventually will require treatment at the rate of approximately one percent per year.

Cytogenetic Abnormalities

• Using Q-banding and/or G-banding techniques and improved methods for inducing leukemia cell proliferation in vitro, the leukemic cells from more than half of all CLL patients have clonal chromosomal abnormalities.

Chromosome 13 Anomalies

• The most common genetic abnormality and one found in about half of all patients is deletion on the long arm of chromosome 13, specifically at 13q14.-23.1 telomeric to the retinoblastoma gene (RB-1) and centromeric to and including the D12S25 region.

• Loss of microRNA miR15 and/or miR16–1 might contribute to leukemogenesis and account for the frequent deletions that are observed at 13q14.3.

Chromosome 12 Anomalies

• Trisomy 12 is the second common abnormality, found in about 20 percent of patients; half of these have trisomy 12 only.

• May not be a primary factor in leukemogenesis, but probably acquired during disease evolution.

Chromosome 11 Anomalies

• Approximately 20 percent of patients have a deletion(s) in the long arm of chromosome 11, termed 11q^–, which is associated with relatively poor prognosis (11q22.3-q.23.1).

• Associated with younger age at diagnosis (< 55 years) and tend to have bulky cervical lymphadenopathy than patients without such genetic changes.

• Higher expression levels of CD38, FMC7, CD25, and surface immunoglobulin, and lower level expression of CD11a/CD18, CD11cd/CD18, CD31, CD48, and CD58.

• Distinct microRNA signatures and characteristic low-level expression of miR-29 and miR-18.

Chromosome 6 Anomalies

• Involve deletions at 6q23 but can also involve deletions at 6q25–27 and/or 6q2.

• 6q21 and 6q24 generally have higher proportions of blood prolymphocytes, higher than average expression of CD38.

• Patients tend to have more aggressive disease than patients with normal cytogenetics or isolated deletions at 13q14.

Chromosome 17 Anomalies

• Deletions in the short arm of chromosome 17 at 17p13.1 are in approximately 10 percent of all patients. The critical gene in the region that typically is deleted is TP5.

• 17p– and/or TP53 mutations generally have more advanced disease, a higher leukemia-cell proliferative rate, a shorter survival, and greater resistance to first-line therapy.

• Neoplastic cells from nearly half of the patients transform to an aggressive B-cell lymphoma (referred to as Richter syndrome or transformation) or B-cell prolymphocytic leukemia may have inactivating mutations in TP53.

Chromosome 14 Anomalies

• t14;18 (or 2;18 and 22;18) translocations involving BCL2 on chromosome 18 are uncommon. However, CLL cells from virtually all cases overexpress BCL2 and this feature is characteristic of low-grade nodular B-cell lymphoma (see Chap. 62).

Chromosome 18 Anomalies

• Five percent have aberrant immunoglobulin gene arrangements with BCL2 located on the long arm of chromosome 18, at 18q21.

Leukemia Cell Growth Kinetics

• In the spleen, proliferation of CLL cells occurs preferentially in the white pulp zones.

• Studies on patients who ingested heavy water to evaluate the growth kinetics of CLL cells in vivo revealed that the leukemic cells of each patient had birth rates ranging from 0.1 percent to greater than 1.0 percent of the entire clone per day.

  — This conflicts with the notion that CLL is principally an accumulative disease as a result of deficient apoptosis.

  — The study suggests that the blood lymphocyte count for any one patient is defined by a more dynamic process, in which leukemia cells are generated and die at appreciable rates.

• Expression of CXCL12 and CXCL13 by marrow stromal cells also could account for the accumulation of leukemia cells in the marrow, which invariably is infiltrated by leukemia cells in untreated patients with CLL.

Immunologic Defects

Immune Deficiency

• Combined immunoglobulin deficiency and impaired cellular immunity

  — Hypogammaglobulinemia is common in active disease.

  — T-cells although not intrinsically involved show impaired reactivity.

  — CLL B cells have little stimulatory activity in autologous or even allogeneic mixed lymphocyte culture and, thus, contribute to the immunodeficiency present in active disease.

• Increased incidence of common bacterial infections.

• Increased risk of opportunistic infections.

• High rate of opportunistic infections posttherapy requires use of prophylactic antibiotics and close monitoring for viral infections (e.g., cytomegalovirus).

• Higher risk of skin cancers.

Autoimmunity

• Autoimmune diseases frequently occur in CLL.

  — Autoimmune hemolytic anemia and immune thrombocytopenia are the most common.

  — Pure red cell aplasia and autoimmune neutropenia are less common.

  — Pathogenic autoantibodies are not produced by the neoplastic B-cell clone.

• Median age of patient at diagnosis is approximately 67 years.

• Male/female ratio is 2:1.

• Twenty-five percent of patients are asymptomatic, and the disease is detected because of lymphocytosis or lymph node enlargement.

• Many patients have fatigue, reduced exercise tolerance, or malaise.

• Some cases may present with chronic rhinitis secondary to nasal involvement of CLL cells.

• Patients with advanced disease may have weight loss, recurrent infections, bleeding, and/or symptomatic anemia.

  — Night sweats and fevers (the so-called B symptoms) are uncommon and should prompt evaluation for complicating infectious disease.

• Lymph nodes may become very large and coalescent.

• Eighty percent of patients have nontender lymphadenopathy at diagnosis.

• Approximately 50 percent have mild to moderate splenomegaly at presentation.

• Extranodal involvement is frequent but not commonly symptomatic.

  — CLL cell infiltrates all can develop in the scalp, subconjuctivae, prostate, gonads, or pharynx.

  — Occasionally, the leukemic cells infiltrate the lung parenchyma, producing nodular or miliary pulmonary infiltrates that can be detected on chest imaging.

  — Gastrointestinal tract also may be infiltrated with leukemic cells and may result in ulceration, gastrointestinal bleeding, or malabsorption.

  — Leukemic cell infiltration of the central nervous system is unusual but may produce headache, meningitis, cranial nerve palsy, obtundation, or coma.

Blood Findings

• The blood cell counts are characterized by an increase in the absolute lymphocyte count of greater than 5.0 × 10⁹/L.

• The blood film has an increase in small, normal appearing lymphocytes to a degree related to lymphocyte count. Characteristically approximately one in six lymphocytes in the blood are CLL cells ruptured during preparation and are referred to as smudge cells.

• Fifteen percent of patients present with normocytic anemia.

• Twenty percent have a positive red cell antiglobulin (Coombs) test at some time in the disease.

• Thrombocytopenia caused by antiplatelet antibodies may develop at any time. In advanced disease, thrombocytopenia also may be a result of marrow replacement and/or splenic sequestration.

Marrow Findings

• Marrow is invariably infiltrated with small lymphocytes in one of four patterns:

  — Interstitial (or lacy): 30 percent. This is associated with a better prognosis and/or early stage disease.

  — Nodular: 10 percent.

  — Mixed interstitial/nodular: 25 percent.

  — Diffuse marrow replacement: 25 percent; associated with a poorer prognosis.

Lymph Node Findings

• Lymph nodes are affected by diffuse infiltrate of small lymphocytes that efface the node architecture and invade the subcapsular sinus.

Immunologic Studies

• Diagnosis of CLL requires sustained monoclonal lymphocytosis of greater than 5 × 10⁹/L.

• The diagnosis of CLL rests on establishing the monoclonal nature of the lymphocytosis. For example, one usually determines if the light chain expression is either λ or κ (monoclonal) and not both (polyclonal).

• CLL cells typically express CD5+, CD10–, CD19+, CD20 (dull), CD23+, and CD103–; low expression of surface immunoglobulin; flow-level or absent expression of CD22 and CD79b.

• Cellular immune defects, possibly related to CLL cell expression of transforming growth factor (TGF)-β and the immune suppressive cell-surface phenotype of leukemia cells.

• FMC7, a monoclonal antibody that binds an epitope of CD20 formed when this surface antigen is present at high density, typically does not react with CLL cells.

• Higher content of cytoplasmic immunoglobulin.

Serum Protein Electrophoresis

• Most common finding is hypogammaglobulinemia.

• Reduction in the serum levels of IgM precedes that of IgG and IgA.

• Five percent of patients have a serum monoclonal protein.

• In some cases, there is defective and/or unbalanced immunoglobulin chain synthesis by the leukemic B-cell clone, resulting in μ heavy-chain disease and/or immunoglobulin light-chain proteinuria (see Chap. 71).

• See Table 56–1 for the immunophenotype of chronic B-cell leukemias/lymphomas.

• Monoclonal lymphocytosis versus causes of polyclonal lymphocytosis (see Chap. 50).

• Prolymphocytic leukemia (see discussion later in this chapter).

  — Fifty-five percent of circulating leukemic lymphocytes should have prolymphocytic morphology; larger size than CLL cells and a prominent nucleolus.

  — High levels of CD79b and surface immunoglobulin; low levels of CD5 (see Table 56–1).

• Hairy cell leukemia (see Chap. 57).

• Lymphomas with circulating neoplastic cells (see Chap. 59).

• Small lymphocytic lymphoma.

  — Low-grade small lymphocytic B-cell lymphoma is closely related to B-cell CLL in its biology and clinical features.

  — Associated with lymph node involvement.

• Mantle cell lymphoma (see Chap. 63).

  — Express many of the same surface antigens as CLL B cells.

  — Does not express CD23.

• Splenic marginal zone lymphoma (SMZL) (see Chap. 64).

  — Commonly is called splenic lymphoma with villous lymphocytes.

  — Mature B-cell phenotype and express IgM and IgD, but typically lack expression of CD23, CD43, CD10, BCL-6, and cyclin D.

  — Neoplastic B cells have weak or negative expression of CD5.

• Lymphomas of follicular center cell origin (see Chap. 62).

  — Small cleaved cell lymphomas express the CD10 (CALLA) antigen.

• Lymphoplasmacytic leukemias.

  — Express CD38, PCA-1, CD56, and CD85; low-level or lack of expression of CD19, CD20, CD24, CD72, and HLA-DR.

• Waldenström macroglobulinemia (see Chap. 70).

• Myeloma (see Chap. 69).

• T-cell lymphoproliferative disorders.

• T-cell CLL and T-cell prolymphocytic leukemia (see discussion later in this chapter).

• Large granular lymphocytic leukemia (see Chap. 58).

• Adult T-cell leukemia/lymphoma (see Chap. 67).

• Cutaneous T-cell lymphomas (see Chap. 66).

Clinical Staging

• Clinical staging is helpful in defining prognosis and deciding when to initiate therapy.

• Rai or Binet staging systems can be used (see Table 56–2 and Table 56–3).

  — Despite the advent of new prognostic markers, these staging systems still have independent prognostic value.

Other Prognostic Indicators

Leukemia Cell Doubling Time (LDT)

• The shorter the time it takes for the lymphocyte count to double, the worse the prognosis.

• If the lymphocyte count doubles in less than 1 year, median survival is about 5 years.

Immunoglobulin Gene Mutation Status

• Two groups are distinguished by the extent that their expressed immunoglobulin heavy chain variable region genes (IgHV) have undergone somatic mutation.

  — Half of all cases have leukemia cells that express nonmutated IgHV genes and have a greater tendency for disease progression.

  — The rest express IgHV genes with levels of base substitutions that distinguish them from their germ-line counterparts.

• One noted exception to this appears to be represented by patients who have leukemia cells that use a particular immunoglobulin gene, designated IGHV3–21.

  — Patients who have CLL cells that use a mutated IGHV3–21 gene together with a λ immunoglobulin light chain encoded IGHV3–21 apparently have a risk of aggressive disease similar to that of patients who have leukemia cells that express unmutated IgHV genes.

CD38

• High cell-surface expression of CD38 is associated with more aggressive disease and/or relatively poor prognosis.

• CD38-negative leukemia cells might later be found to have leukemia cells that express this surface antigen.

Zeta-Associated Protein of 70kDa (ZAP-70)

• CLL cases that use unmutated IGHV genes generally express levels of ZAP-70 comparable to normal T cells.

• CLL cases that use mutated IGHV genes generally do not express detectable levels of ZAP-70.

• CLL-cell expression of ZAP-70 appears to be a stronger prediction of need for early treatment than use of unmutated IGHV.

Serum Factors

• High-level in CLL cells of β₂-microglobulin (β₂M) is associated with adverse prognosis.

Indications for Treatment (See Table 56–4)

• Rai stage 0 to I, or Binet A should be monitored without therapy, unless they have evidence of progressive disease.

• Progressive disease:

  — An increase of 50 percent or more in blood lymphocyte count over a 2-month period or LDT of less than 6 months.

  — Transformation of CLL cells to a more aggressive histology causing worsening anemia and/or thrombocytopenia.

  — Increase of 50 percent or more in the size of the liver and/or spleen.

  — An increase of 50 percent or more on two consecutive exams performed about 2 weeks apart in the sum of the sizes of at least two lymph nodes, one of which must be greater than 6 cm.

  — Appearance of new palpable lymphadenopathy.

• Absolute lymphocyte count should not be used as the sole indicator for treatment.

• Stable disease:

  — Patients who do not achieve a complete or partial response and who do not have progressive disease.

Response Criteria

• Response criteria for patients who have had prior therapy are the same as those used for initial therapy.

• Four major response criteria:

  — Complete response.

  — Partial response.

  — Nonresponse.

  — Progressive disease.

• Incomplete marrow recovery (CRi): patients who fulfill all criteria for complete response except for persistent anemia, thrombocytopenia, or neutropenia unrelated to CLL.

• A patient is defined as having a relapse if they achieved complete or partial response but experienced disease progression 12 or more months after completing therapy.

Complete Response

• Requires that the patient is free of clinical disease for at least 2 months after therapy.

• Normal complete blood counts, e.g., neutrophil count at least 1.5 × 10⁹/L, lymphocyte count less than or equal to 4.0 × 10⁹/L, platelets greater than or equal to 1.0 × 10¹¹/L, and hemoglobin greater than 11 g/dL without transfusion.

• Absence of fever, night sweats, weight loss, or other disease-related symptoms.

• Absence of hepatosplenomegaly or detectable adenopathy.

• Marrow with less than 30 percent lymphocytes and lacking pathologic lymphoid nodules.

• If the marrow is found to be hypocellular, a repeat marrow biopsy should be performed after 4 to 6 weeks, provided blood counts have recovered. A marrow biopsy should not exceed 6 months after the last treatment.

Partial Response

• For at least 2 months after therapy, the patient must have at least:

  — A 50 percent reduction in the number of blood lymphocytes.

  — A 50 percent reduction in lymphadenopathy or hepatosplenomegaly.

• Absolute neutrophil count of greater than or equal to 1.5 × 10⁹/L or greater than 50 percent improvement over that noted prior to therapy.

• Blood platelets greater than 100 × 10⁹/L.

• Hemoglobin greater than 11 g/dL.

• A 50 percent improvement in platelet or red cell counts over pretreatment values without transfusion.

• Patients who satisfy the criteria for a complete response but who have persistent lymphoid nodules in the marrow are classified as having a nodular partial response.

Progressive Disease

• Develop new lymphadenopathy; an increase in lymphadenopathy by greater than or equal to 50 percent.

• An increase in the liver or spleen size by greater than 50 percent or the appearance of hepatomegaly or splenomegaly while on therapy.

• An increase in the absolute lymphocyte count by greater than or equal to 50 percent.

• Transformation to a more aggressive histology (e.g., Richter syndrome), which should be established by lymph node biopsy.

Refractory Disease

• Patient who experiences disease progression within 6 months of completing therapy is considered to have disease that is refractory to such therapy.

Minimal Residual Disease (MRD)

• Improved leukemia-cell detection methods using flow cytometry or polymerase chain reaction (PCR) can reveal patients in complete response who have residual leukemia cells.

• Patients who experience eradication of MRD apparently have a longer treatment-free survival than do patients who have achieved a complete response but have persistent MRD.

Cytogenetics and Type of Therapy

• Del(17p) predicts resistance to standard chemotherapy and thus an inferior prognosis.

• Del(11q) has significantly lower response rates to single-agent chemotherapy (e.g., chlorambucil or fludarabine monophosphate).

  — Response of such patients to treatment with a combination drug regimen using an alkylating agent, such as cyclophosphamide, with a purine analogue, such as fludarabine monophosphate, did not differ significantly from that of patients who have CLL cells that lack this deletion.

Age and Type of Therapy

• Treatment regimens found safe and well tolerated in clinical trials might prove too toxic for older patients treated in the community.

• Cumulative Illness Rating Scale: evaluate the burden of comorbidity on elderly cancer patients:

  — "GO GO": Patients who are medically fit with no or just mild comorbidities and a normal life expectancy.

  — "SLOW GO": Patients who are medically less fit with multiple or severe comorbidities and an unknown life expectancy.

  — "NO GO": Patients who are frail and had fatal comorbidities and a very short life expectancy.

Therapeutic Agents

Deoxyadenosine Analogues

Fludarabine (9-β-D arabinofuranosyl-2-fl uoradenine, F-ara-A)

• Inhibits adenosine deaminase (ADA). (9-β-D arabinofuranosyl-2-fluoradenine, F-ara-A).

• Most widely used deoxyadenosine analogue in the treatment of CLL.

• Complete and partial responses achieved in 50 to 60 percent of previously treated patients, and in 70 to 80 percent of untreated patients, at a dose of 25 mg/m² intravenously per day for 5 consecutive days each 28-day cycle.

• An oral formulation of fludarabine has been approved for use in North America and Europe

  — The recommended adult dose in single-agent therapy is 40 mg/m² for 5 consecutive days each 28-day cycle, which is equivalent to the 25mg/m² intravenous dose.

• Patients who do not respond to two cycles of therapy are unlikely to respond to further cycles of fludarabine as single-agent therapy.

• Ability to prolong survival is not established.

• Major toxicities are hematologic (e.g., cytopenias) and immunologic (e.g., increased susceptibility to infection).

• Renal clearance represents approximately 40 percent of the total-body clearance, which can also be achieved via hemodialysis in patients who experience acute renal failure after drug therapy.

• Should not be administered to patients with a glomerular filtration rate of less than 17 mL/min per m².

Cladribine (2-chlorodeoxyadenosine)

• Resistant to ADA with similar activity spectrum as that of fludarabine.

• Forty to 60 percent of patients respond to monthly cycles of cladribine per oral (PO) at 0.12 mg/kg daily for 5 consecutive days.

• Patients resistant to fludarabine generally are also resistant to cladribine as single-agent therapy.

• Thrombocytopenia may be dose limiting.

• Myelotoxicity and impaired cellular immunity similar to that of fludarabine.

• Ability to prolong survival is not established.

• Median duration of partial remissions is 9 months; nonresponding patients have a short median survival of 4 months.

Pentostatin (2′-deoxycoformycin)

• Inhibits ADA.

• Generally is administered at a dose of 4 mg/m² weekly for 3 weeks followed by 4 mg/m² every other week for 6 weeks, followed by once a month for 6 months.

• More than 90 percent of the administered drug is excreted unchanged in the urine.

Alkylating Agents

Chlorambucil

• Daily oral dose, initially 2 to 4 mg, up to 6 to 8 mg/d; can be advanced to 6 to 8 mg if tolerated.

• Intermittent schedule, total dose 0.4 to 0.7 mg/kg given over 1 to 4 days every 2 to 4 weeks or on day 1. Cycle repeated every 2 to 4 weeks.

Bendamustine (Treanda)

• Administered at 70 to 100 mg/m² given intravenously on each of 2 consecutive days every 4 weeks demonstrated overall response rates of 50 to 90 percent and complete response 10 to 30 percent in patients with relapsed/refractory CLL.

• A phase III trial comparing the activity of chlorambucil versus bendamustine in the initial therapy of 319 patients with CLL demonstrated significantly higher response rates in patients treated with bendamustine.

• Myelosuppression is the major toxicity.

• For patients who experience grade 3 or greater hematologic toxicity following treatment, it is recommended that the dose be reduced to 50 mg/m² on days 1 and 2 of each cycle.

• If grade 3 hematologic toxicity recurs, then further reduction of the dose to 25 mg/m² on days 1 and 2 should be considered.

• In the event of grade 4 hematologic toxicity or clinically significant grade 2 or higher nonhematologic toxicity, then treatment should be delayed until such toxicity has resolved, or at the discretion of the treating physician.

• Not recommended for treatment of patients with a glomerular filtration rate of less than 23 mL/min per m².

Cyclophosphamide

• As active as chlorambucil.

• Daily oral dose, 50 to 100 mg.

• Intermittent schedule with 500 to 750 mg/m² given orally or intravenously every 3 to 4 weeks.

• Fluid intake of 2 to 3 L per day important while taking cyclophosphamide to decrease risk of hemorrhagic cystitis.

Alemtuzumab (Campath-1H)

• Also known as MabCampath or Campath.

• Humanized monoclonal antibody specific for CD52.

Relapse/Refractory CLL

• Approved for use in patients refractory to fludarabine as single-agent therapy.

• Patients typically are given successively increasing doses 1 mg, 3 mg, 10 mg, and then 30 mg per intravenous injection to mitigate the infusional reactions of fever, chills, and/or rash, which generally are more pronounced during the initial administrations of this antibody.

• Grade 4 neutropenia is not uncommon, but is not an indication to discontinue treatment.

• Overall response rate of approximately 30 percent and complete response rate of 2 percent.

• Acute toxicity with infusion includes rigors, hypotension, rash, and dyspnea.

• Generally not effective for reducing lymphadenopathy.

• Causes profound T-cell depletion and immunosuppression.

• Acute infusional toxicity can be mitigated by preinfusion hydrocortisone at a dose of 100 mg intravenously and by initiating therapy with smaller doses that are increased on subsequent treatment days, if the lower dose is well tolerated (e.g., 3 mg per dose, then 10 mg per dose, and then 30 mg per dose).

• Treated patients have an increased susceptibility to opportunistic infections (esp. cytomegalovirus), and should receive concomitant antimicrobial therapy in prophylaxis against infection.

• Patients with bulky lymphadenopathy (greater than 5 cm in diameter) appear unlikely to achieve a complete response to therapy with this agent.

Initial Therapy

• Yields a longer progression-free survival duration than does single-agent chlorambucil.

• Campath has a complete response rate of 24 percent, an overall response rate of 83 percent, and time-to-progression requiring alternative treatment of 23.3 months, which were significantly superior to the complete response rate of 2 percent, OR rate of 55 percent, and time-to-progression of 14.7 months observed in the patients treated with chlorambucil.

• The US Food and Drug Administration (FDA) approved intravenous alemtuzumab for use in the initial therapy of patients with CLL in September 2007.

Subcutaneous Administration

• Administered subcutaneously at 30 mg three times per week for 6 or more weeks.

• Blood concentrations of alemtuzumab achieved following subcutaneous administration were significantly lower than those observed following intravenous administration of the same amount of antibody.

• Requires longer treatment durations and/or greater amounts of alemtuzumab to achieve comparable clinical responses as intravenous alemtuzumab.

• Not FDA approved.

• Adverse events include grade 1 or 2 local bruising and discomfort at site of injection.

Rituximab (anti-CD20)

• Humanized monoclonal antibody specific for CD20.

• Studies using single-agent rituximab at a dose of 375 mg/m² intravenously each week for 4 weeks noted only partial responses and in a minority of CLL patients.

• Several clinical trials have demonstrated therapeutic benefit (see Table 56–5).

• Responses observed are generally partial, limited to lymph nodes with median time to progression of less than 8 months.

• Toxicity at high dose is extremely common but is generally at grade 1 or 2 (fevers and chills).

• The severity of and risk for infusion-related reactions abate with successive infusions.

• Problems related to the initial treatment can be mitigated by slowing the rate of infusion and by splitting the first dose, giving 100 mg rituximab on the first day and then the remainder of the 375 mg/m² dose on day 2.

Glucocorticoids

• For treatment of associated autoimmune diseases; 1 mg/kg daily, and then taper.

• Partial responses can be achieved with intravenous high-dose methylprednisolone at 1 g/m² per day for 5 days at monthly intervals.

• Prednisone, as a single agent, can control disease in approximately 10 percent of patients.

Other Agents

• Cytosine arabinoside: High-dose cytosine arabinoside has modest activity in advanced-stage CLL.

• Etoposide: Patients who do not respond to alkylating agents can achieve a partial remission.

• Mitoxantrone has apparent activity in CLL.

Combination Therapy

Chlorambucil and Prednisone

• The standard regimen when initiating treatment has been:

  — Chlorambucil 0.4 to 0.7 mg/kg orally on day 1.

  — Prednisone 80 mg orally days 1 to 5.

  — Repeat every 2 to 4 weeks.

• Eighty percent of patients may achieve partial or complete responses.

Fludarabine-Containing Regimens

Fludarabine and Cyclophosphamide (FC)

• Can induce responses in patients who appear resistant to single-agent fludarabine.

• Each 28-day cycle consists of fludarabine 20 mg/m² to 30 mg/m² intravenously daily (or 30-50mg/m² orally) for 3 days and cyclophosphamide intravenously or orally at 200 mg/m² to 300 mg/m² daily for 3 days.

• A response rate is seen in virtually all patients, but approximately 25 percent achieve complete remission.

• Higher degree of myelotoxicity than with either agent alone.

Fludarabine/Cyclophosphamide/Rituximab (FCR)

• Treatment with rituximab concomitant with fludarabine and cyclophosphamide (FCR) appears highly effective (Tables 56–6 and 56–7).

• When given at 375 mg/m² on day 1 of course 1 and then at 500 mg/m² on day 1 of courses 2 to 6, rituximab when used with fludarabine/cyclophosphamide induced complete response rate of 25 percent and overall response rate of 73 percent of previously treated patients.

• Thirty-two percent of the patients who achieved a complete response did not have evidence of MRD in the marrow by molecular testing.

• Large multicenter phase II trial established superiority of FCR over FC (see Table 56–6).

• Major toxicity of FCR is hematologic.

Fludarabine/Rituximab (FR)

• Appears well tolerated and more effective than treatment with single-agent fludarabine.

• Significantly better progression-free survival and overall survival than patients treated with fludarabine alone in long-term follow-up.

Fludarabine Regimens with Mitoxantrone

• Treatment with mitoxantrone, given at 10 mg/m² on the first day of each cycle, together with fludarabine, given at 30 mg/m² on days 1 through 3 of a 28-day cycle.

• Overall response rates of 80 percent in previously untreated patients and 60 percent in patients who were refractory to therapy with alkylating agents.

• The regimen of fludarabine at 25 mg/m² given on days 1 through 3 of a 28-day cycle together with cyclophosphamide at 200 mg/m² on days 1 through 3 and mitoxantrone, given at 10 mg/m² on the first day of each cycle, yielded complete responses of 50 percent (and overall responses of 78%) after a median of 3 cycles in patients who had relapsed or who were resistant to standard therapy.

Fludarabine Regimens Containing Cisplatin or Oxaliplatin (OFAR Regimen)

• Cisplatin, administered at 100 mg/m² via continuous intravenous infusion over 4 days, has been used in combination with fludarabine given at 30 mg/m² via bolus intravenous infusion on days 3 and 4 of a 28-day cycle.

• Myelosuppression was the major dose limiting toxicity.

• The combination regimen involving use of oxaliplatin, fludarabine, cytarabine, and rituximab (OFAR) has activity in patients with relapsed/refractory CLL or Richter transformation.

• A phase I/II study determined the optimal dose of oxaliplatin at 25 mg/m² given intravenously on days 1 to 4 of each 28-day cycle.

• Intravenous fludarabine (at 30 mg/m²) and cytarabine (1 g/m²) are given on days 2 and 3 of each cycle along with rituximab, given at 375 mg/m² on day 3 of cycles 1 and then day 1 of each subsequent cycle.

Fludarabine/Prednisone

• Concomitant use of prednisone with fludarabine does not improve the response rate, but does increase the risk for opportunistic infection.

Fludarabine/Chlorambucil

• Treatment with this combination has not been shown to be significantly better than that with fludarabine alone.

Pentostatin-Containing Regimens

• Response frequencies similar to that of fludarabine-containing regimens that use otherwise similar agents.

• Treatment of previously treated patients with pentostatin at 4 mg/m² and cyclophosphamide at 600 mg/m² given on day 1 of each 21-day course.

  — Complete response rate is approximately 15 percent; overall response rate is approximately 75 percent in fludarabine-refractory patients.

• Pentostatin administered with cyclophosphamide and rituximab:

  — Effective for patients with relapsed CLL and in patients who have not received prior therapy.

Cladribine-Containing Regimens

• Response rates to 3 courses of cladribine at 4 mg/m² per day and cyclophosphamide 350 mg/m² per day for 3 days every 4 weeks in patients with refractory or recurrent CLL appeared inferior to those achieved in comparable patients treated with the combination of fludarabine and cyclophosphamide.

• Incorporation of rituximab into cladribine-containing regimens improves the effectiveness of therapy without substantially adding to treatment-related toxicity.

High-Dose Methylprednisolone and Rituximab

• The combination of high-dose methylprednisolone and rituximab (HDMP + R) appears highly active in the treatment of patients with refractory CLL, as well as in patients who had not received prior therapy.

• Does not employ agents that can cause significant myelosuppression.

• Fourteen patients with fludarabine-refractory CLL received 1 g/m² per day of intravenous methylprednisolone for 5 days on days 1 to 5 of each 28-day cycle together with rituximab at 375 mg/m² weekly for the 4 weeks of each cycle. Following three 4-week cycles of therapy, the treated patients experienced a complete remission rate of 36 percent and an overall response rate of 79 percent.

• HDMP reduced to 3 days per 28-day cycle, with the same dose of rituximab yielded an overall response rates of 96 percent and a complete response rate of 32 percent after 3 cycles of therapy for patients who had not received prior therapy.

Cyclophosphamide, Vincristine, and Prednisone (CVP)

• Effective in previously untreated patients and in some with refractory CLL.

• The dosages are cyclophosphamide 300 to 400 mg/m², orally, daily for 5 days, vincristine 1 to 2 mg intravenously on day 1, and prednisone 40 mg/m² orally per day for 5 days.

Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP)

• Has been evaluated in patients with advanced disease, but appears to have a lower therapeutic index than purine-analog-containing chemotherapy regimens.

• Mean survival of patients treated with CHOP was similar to that of patients who received CVP over an 18-month period.

• Vincristine does not appear to add substantially to the CHOP regimen.

Splenectomy

• May ameliorate the cytopenias associated with advanced-stage CLL, particularly thrombocytopenia.

• May be effective in mitigating intractable or recurrent disease-associated autoimmune hemolytic anemia and/or thrombocytopenia, providing for sustained improvement in the majority of patients who undergo this procedure.

Radiation Therapy

• Irradiation remains a useful technique for localized treatment to ameliorate symptoms caused by nerve impingement, vital organ compromise, painful bone lesions, or bulky disfigurement.

• Delivery of 200 Gy can result in rapid shrinkage of lymph nodes or masses.

• Splenic irradiation is useful in patients with painful splenomegaly.

Leukapheresis

• May reduce organomegaly and improve hemoglobin and platelet levels.

• Successful in ameliorating lymphocytosis and disease-related complications in pregnant patients with CLL, obviating the use of other antileukemia treatments until late pregnancy (when risk to the fetus is minimized) or after delivery.

Supportive Measures

• Erythropoietin:

  — Used on patients who develop anemia as a disease-related complication.

  — May obviate or reduce the frequency of blood transfusions.

  — Can be associated with serious therapy-related complications, such as skin reactions, polycythemia, or thromboembolic disease.

Investigational Therapies

Hematopoietic Stem Cell Transplantation (HSCT)

Autologous HSCT

• Preparative regimen well tolerated.

• High risk for recurrent disease after transplant.

• May prolong disease-free survival.

Allogeneic HSCT

• May eradicate the leukemia cells to the levels that cannot be detected using sensitive molecular techniques to detect clonal immunoglobulin gene rearrangements.

• Patients who relapse following allogeneic HSCT may respond to infusions of donor leukocytes.

• Patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year overall survival of 71 percent.

Nonmyeloablative Allogeneic HSCT

• Preparative regimen better tolerated than standard allogeneic HSCT.

• Complete chimerism, as well as best response, is not achieved immediately after transplantation but may take over 3 months to develop.

• Patients with refractory CLL can experience eradication of MRD several weeks following transplant, providing evidence of a graft-versus-leukemia effect.

Other Agents and Biologics

Flavopiridol (Alvocidib)

• Cyclin-dependent kinase inhibitor that has activity in CLL.

Lenalidomide (Revlimid)

• Patients with CLL appear more sensitive to lenalidomide than patients with other conditions.

  — Resulted in unacceptable toxicity when given at doses typically used in the treatment of myeloma.

Ofatumumab (Arzerra)

• Ofatumumab is a human monoclonal antibody (for the CD20 protein) that appears to inhibit early-stage B lymphocyte activation.

• Approved by the FDA in October of 2009 for use in treating patients with CLL refractory to fludarabine and alemtuzumab.

Active Immune Therapy and Gene Therapy

• Treatment of patients with autologous leukemia cells transduced with Ad-CD154 showed promising results in a phase I clinical study.

Disease Complications

Infection

• Major cause of morbidity/mortality.

• Susceptibility to infection correlates with hypogammaglobulinemia and/or T-cell lymphocytopenia.

  — Advanced-stage disease, hypogammaglobulinemia, and low levels of specific antibodies to pneumococcal capsular polysaccharide associated with greatest of severe or multiple infections.

• Monthly intravenous administration of pooled normal serum immunoglobulin (IVIG at 240 to 400 mg/kg every 3 to 4 weeks) can decrease frequency of infection.

• Autoimmune hemolytic anemia and immune thrombocytopenia.

Second Malignancies

• Most frequently melanoma, sarcoma, colorectal, lung, or myeloma.

• Higher recurrence rates of basal cell carcinoma after Mohs surgery (a surgical procedure used to treat common types of skin cancer) than the general population.

• Higher incidence of developing Merkel cell carcinoma (rare and highly aggressive cancer in which malignant cancer cells develop on or just beneath the skin and in hair follicles).

• Higher risk for developing more aggressive and/or metastatic squamous cell skin carcinomas than the general population.

• Multiple myeloma occurs at 10 times the expected rate in patients with CLL but evidently does not arise from the same malignant B-cell clone.

• Both untreated and treated CLL patients can develop acute myelogenous leukemia or myelodysplastic syndrome.

• Therapy-related acute myelogenous leukemia may develop after treatment with single-agent deoxyadenosine analogues, such as fludarabine or cladribine.

Pure Red Cell Aplasia

• Patients with CLL or ALL may develop pure red cell aplasia that is unrelated to therapy.

• For CLL patients, treatment with the combination of cyclosporine and prednisone appears to be superior to prednisone alone.

Richter Transformation

• Transformation to an aggressive, large cell, high-grade, B-cell lymphoma.

• Can occur at any time in the course of CLL.

• Occurs in approximately 3 percent of patients at a median of 2 years after diagnosis of CLL.

• Can develop in patients who had not received chemotherapy.

• Can arise from the original CLL clone.

• Chromosomal abnormalities are complex and include:

  — del 8p, del 9p, del 11q (11q23), 12(+), del 13q, 14q(+), del 17p, del 20 and/or translocations involving chromosome 12.

  — Trisomy 12 and chromosome 11 abnormalities are more frequent.

• Higher incidence of P53 mutations at transformation.

• Three independent risk factors for transformation identified:

  — High-level expression of CD38 by leukemia B cells.

  — Absence of leukemia-cell deletion at 13q14.

  — Leukemia cell expression of certain IgHV genes, notably IGHV4-39.

• Clinical and laboratory features:

  — Increased serum lactic acid dehydrogenase activity in approximately 80 percent of patients.

  — Rapid lymph node enlargement in approximately 65 percent.

  — Fever and/or weight loss in approximately 60 percent.

  — Monoclonal gammopathy in approximately 45 percent.

  — Extranodal disease in approximately 40 percent.

• Not all patients with CLL that have rapid lymph node enlargement have Richter transformation.

• Infection with herpes simplex virus can cause acute lymphadenitis.

• Occasional cases of Richter transformation have histology resembling that of Hodgkin lymphoma (see Chap. 59), termed Richter syndrome with Hodgkin lymphoma features.

  — Richter syndrome with Hodgkin lymphoma features may respond favorably to therapy for Hodgkin lymphoma.

• Treatment similar to that of patients with high-grade lymphoma (see Chap. 61).

• Encouraging responses have been observed with OFAR regimen (see above).

• Median survival is 5 months after transformation.

CLL/PL and Prolymphocytic Transformation

• Fifteen percent of patients with CLL have a mixture of small lymphocytes and prolymphocytes (PL), the latter accounting for 10 to 50 percent of the lymphoid cells. These patients are considered to have CLL/PL.

• In eighty percent of CLL/PL cases, the proportion of PLs remains stable.

• Twenty percent of patients with CLL/PL undergo prolymphocytic transformation with greater than 55 percent of the leukemia cells having PL morphology (see below).

  — Progressive splenomegaly is characteristic.

  — Mean survival of 9 months after transformation.

Acute Lymphoblastic Leukemia

• Rare complication.

• Can arise from same cell clone as CLL.

• Associated with high levels of expression of c-MYC and surface immunoglobulin.

Prognosis

• No established cures for CLL.

• Spontaneous remissions are rare.

• Varies substantially between different patients depending on clinical stage and/or presence or absence of certain disease features associated with progression and/or adverse clinical outcomes.

• Female patients have longer survival.

• Male-to-female ratio is greater in patients diagnosed at younger ages (< 65 years).

• CLL relegated deaths occur more frequently in younger patients.

• Five-year relative survival is approximately 70 percent, 70 percent, 65 percent, and 40 percent for age groups younger than 40, 40 to 59, 60 to 79, and 80+ years, respectively, indicating that the 5-year survival does not vary significantly between the different age groups under the age of 80 years.

• Risk of CLL-unrelated deaths and secondary malignancies predominated older groups.

Prognostic Nomogram and Index for Overall Survival

• Can assist in predicting survival of untreated patients.

• Uses six independent covariates that were identified in a multivariate Cox proportional hazards assessment of outcomes data (see Table 56–8).

• Allows one to total the points identified on the top scale for each independent covariate (see Table 56–9).

• Total point score is then identified on a total point scale and based on the score the patients can then be stratified into low-risk, intermediate-risk, or high-risk categories (see Fig. 56–1).

Definition

• Clinical and morphologic variant of CLL.

• Subacute lymphoid leukemia.

• Incidence: less than 10 percent that of CLL.

• Diagnosis of PLL requires that at least 55 percent of the circulating leukemic lymphocytes have prolymphocytic morphology.

Etiology and Pathogenesis

• Unknown etiology.

Cytogenetics

• Karyotype of the leukemia cells from many patients displays the 14q+ abnormality.

• Trisomy 12 is another recurrent abnormality.

• Deletions of the long arm of chromosome 6 (6q-) and rearrangement affecting chromosomes 1 and 12 are occasionally observed.

• Most common abnormalities:

  — 13q14 at 46 percent.

  — Trisomy 12 at 21 percent.

  — 14q32 at 21 percent.

• Loss of heterozygosity at 17p13.3 associated with inactivating mutations in the TP53 gene is observed in as many as three-quarters of the cases examined.

Cytogenesis

• Mature B-cell origin that have undergone immunoglobulin gene rearrangement.

  — IGHV4-34 genes.

Clinical Features

• Fifty percent of patients are older than 70 years.

• Often have advanced disease at presentation.

• Presenting symptoms include fatigue, weakness, weight loss, an acquired bleeding tendency, and early satiety because of splenomegaly.

• Massive splenomegaly occurs in about two-thirds of patients.

• Patients typically have relatively little palpable lymphadenopathy.

• In rare cases, patients may present with leukemic meningitis, leukemic pleural effusion, or malignant ascites.

Laboratory Features

• Frequently find normochromic, normocytic anemia with hemoglobin levels less than 11 g/dL.

• Platelet count is often less than 100 × 10⁹/L.

• Lymphocyte count is greater than 100 × 10⁹/L in 75 percent of patients.

• Hypogammaglobulinemia is common, and about one-third of patients have monoclonal gammopathy.

• Marrow is infiltrated diffusely with neoplastic lymphocytes.

• PLL cells typically express B-cell differentiation antigens and:

  — Variable levels of CD5 (only about half of all cases are CD5⁺).

  — Generally express high levels of sIg, usually IgM or IgD and react strongly with antibody FMC7.

  — High levels of CD22 and are often negative for CD23.

Therapy, Course, and Prognosis

• Indications for treatment:

  — Disease-related symptoms.

  — Symptomatic splenomegaly.

  — Progressive marrow failure.

  — Blood prolymphocyte count greater than 20 × 10⁹/L.

  — Hemoglobin less than 10 g/dL in the absence of hemolysis.

  — Platelet count less than 100 × 10⁹/L.

• Treatment is with alkylating agents similar to those used for CLL, or combinations such as CHOP, yield response rates of 20 percent.

• Fludarabine or cladribine may be effective.

• Monoclonal antibodies (e.g., CAMPATH-1H, rituximab), alone or in combination with chemotherapy, may be effective.

• Splenic irradiation with 1000 to 1600 Gy delivered to the splenic bed, has been advocated as a palliative therapy for the disease.

Definition

• Because of its relative aggressive clinical behavior, what formerly had been called T-cell CLL is categorized in the REAL classification as T-cell prolymphocytic leukemia (PLL) regardless of leukemia cell morphology (see Chap. 54).

• Incidence: less than 5 percent that of CLL.

Etiology and Pathogenesis

• Unknown etiology.

• There is a 3:2 male to female predominance.

• Incidence is five to six times higher in the southern islands of Japan than in Western societies.

• Infection with human T-lymphotropic virus type I (HTLV-1) may play a pathogenic role in a subset of patients.

Genetics

• Chromosomal regions most often overrepresented were:

  — 8q at 75 percent, 5p at 62 percent, and 14q at 37 percent, as well as 6p and 21 both at 25 percent.

• Chromosomal regions most often underrepresented were:

  — 8p and 11q at 75 percent, 13q at 37 percent, and 6q, 7q, 16q, 17p, and 17q at 25 percent.

• Less common cytogenetic rearrangements are:

  — del(6)t(X;6), (p14;q25), del(13)t(13;14)(q22;q11), t(5;13)(q34;p11), r(17)(p13q21), and t(17;20)(q21;q13).

• Alterations on chromosomes 5, 6, 8, 11, 13, 14, 17, and/or 21 apparently cluster into discrete regions that may contain genes that are deleted or amplified during leukemogenesis or disease progression.

• Strong association with mutations in the ataxia-telangiectasia–mutated (ATM) gene that maps to chromosome region 11q22.3–23.1.

• MCP1 or TCL1 on the short arms of chromosome 13 and 14, respectively, are implicated in the pathogenesis of T-PLL.

Clinical Features

• Presenting symptoms include fatigue, weakness, weight loss, and early satiety because of splenomegaly.

• About a third of patients have cutaneous involvement on the torso, arms, and face, which is usually present at diagnosis.

• Skin manifestations include diffuse infiltrated erythema and erythroderma, producing a nonscaling, papular, nonpruritic rash.

• Some cases present with central nervous system involvement.

Laboratory Features

• Blood lymphocyte counts often in excess of 10 × 10⁹/L at presentation.

• T-lymphocyte infiltration of the marrow.

• Biopsy of erythematous skin lesions can reveal a perivascular or periappendiceal dermal infiltrate of lymphoid cells, often with prolymphocyte morphology.

• Leukemia cells typically express pan-T-cell differentiation antigens (e.g., CD2, CD3, CD5, and CD7), but not CD1, HLA-DR, or terminal transferase, reflecting a mature T-cell phenotype.

• In addition to pan-T-cell surface antigens, approximately:

  — Seventy-five percent of cases express CD4 (helper T-cell phenotype), but not CD8.

• Fifteen percent of cases express CD8 (suppressor/cytotoxic T-cell phenotype) but not CD4.

• Ten percent of cases express both CD4 and CD8 (less-mature T-cell phenotype).

• Leukemia cells have monoclonal T-cell receptor gene rearrangements.

Differential Diagnosis

Polyclonal T-Cell Lymphocytosis

• Cells typically are a mixture of CD4⁺/CD8^– and CD4^–/CD8⁺ T cells and lack monoclonal T-cell receptor gene rearrangements.

T-Cell Large-Granular Lymphocytic Leukemia

• Leukemia cells have large granular lymphocyte morphology (see Chap. 58).

Adult T-Cell Leukemia/Lymphoma

• Endemic to the southwest of Japan and the Caribbean region (see Chap. 67).

• Patients have lymphadenopathy, hypercalcemia, and high white blood cell counts.

• Leukemia cells have polylobed or convoluted nuclei.

• Patients typically have antibodies to HTLV-I.

Mycosis Fungoides and Sézary Syndrome

• Neoplastic cells have characteristic cerebriform nuclei (see Chap. 66).

• Shares many features with T-cell PLL.

Therapy, Course, and Prognosis

• Aggressive disease that is generally refractory to conventional alkylating agent chemotherapy.

• Treatment with deoxyadenosine analogues (e.g., 4 mg/m² each week for the first 4 weeks and then every other week or cladribine) is effective in inducing complete response or partial response in about half of patients.

• Topical glucocorticoids, mechlorethamine, carmustine, ultraviolet light B, PUVA, or total skin electron beam therapy is palliative for patients with extensive cutaneous involvement (see Chap. 66).

• Clinical trials have found that alemtuzumab induced responses in more than two-thirds of heavily pretreated relapsed/refractory patients with T-cell PLL.

• Systemic glucocorticoids may be palliative.

• High-dose chemoradiotherapy and allogeneic stem cell transplantation has had anecdotal success.

• Median survival is approximately 3 years for patients with PLL and 8 years for those with CLL.